A great number and variety of biologically active agents are known in the art to have therapeutic benefits when delivered appropriately to a patient having a condition upon which such biologically active agents can exert a beneficial effect. These biologically active agents comprise several broad classes, including, but not limited to peptides or proteins, such as hormones, proteins, antigens, repressors/activators, enzymes, and immunoglulins, among others. Therapeutic applications include treatment of cancer, hypercalcemia, Paget's disease, osteoporosis, diabetes, cardiac conditions, including congestive heart failure, sleep disorders, Chronic Obstructive Pulmonary Disease (COPD) and anabolic conditions, to name a few.
In the art, formulating such biologically active agent formulations in a therapeutically effective and commercially viable manner has been problematic, due in part, to the tendency of many biologically active agents to deteriorate in the presence of oxygen and water. Particularly susceptible to oxidation include the amino acids methionine and cysteine. Water causes degradation of large number of biological agents. This affects particularly peptides and proteins as a result of hydrolysis of the amide bond.
References have been published which discuss the effects of oxidation and hydrolysis on biologically active agents during manufacture and storage. For example, Pikal M J, Dellerman K, Roy M L. Formulation and stability of freeze-dried proteins: effects of moisture and oxygen on the stability of freeze-dried formulations of human growth hormone. Dev Biol Stand. 1992; 74:21-38; Lai, Mei C.; Hageman, Michael J.; Schowen, Richard L.; Borchardt, Ronald T.; Topp, Elizabeth M. Chemical Stability of Peptides in Polymers. 1. Effect of Water on Peptide Deamidation in Poly(vinyl alcohol) and Poly(vinyl pyrrolidone) Matrixes. Journal of Pharmaceutical Sciences (1999), 88(10), 1073-1080, address how biological active agents experience deterioration due to oxidation or hydrolysis when exposed to air or water over extended periods of time.
The deterioration of biologically active agents in formulations is particularly problematic when biologically active agents are administered by transdermal delivery. The word “transdermal”, as used herein, is a generic term that refers to delivery of an active agent (e.g., a therapeutic agent, such as a drug, pharmaceutical, peptide, polypeptide or protein) through the skin to the local tissue or systemic circulatory system without substantial cutting or penetration of the skin, such as cutting with a surgical knife or piercing the skin with a hypodermic needle. Transdermal agent delivery includes delivery via passive diffusion as well as delivery based upon external energy sources, such as electricity (e.g., iontophoresis) and ultrasound (e.g., phonophoresis).
Numerous transdermal agent delivery systems and apparatus have been developed that employ tiny skin piercing elements to enhance transdermal agent delivery. Examples of such systems and apparatus are disclosed in U.S. Pat. Nos. 5,879,326, 3,814,097, 5,250,023, 3,964,482, Reissue No. 25,637, and PCT Publication Nos. WO 96/37155, WO 96/37256, WO 96/17648, WO 97/03718, WO 98/11937, WO 98/00193, WO 97/48440, WO 97/48441, WO 97/48442, WO 98/00193, WO 99/64580, WO 98/28037, WO 98/29298, WO 98/29365 and US Publication Nos. US2004/0062813, US2004/0265354, US2005/0090009, US2005/0106209, US20050123507, US2005/0226922, US2005/0256045, and US2005/0266011; all incorporated herein by reference in their entirety.
The disclosed systems and apparatus employ piercing elements of various shapes and sizes to pierce the outermost layer (i.e., the stratum corneum) of the skin, and thus enhance the agent flux. The piercing elements generally extend perpendicularly from a thin, flat member, such as a pad or sheet. The piercing elements are typically extremely small, some having a microprojection length of only about 25-400 microns and a microprojection thickness of only about 5-50 microns. These tiny piercing/cutting elements make correspondingly small microslits/microcuts in the stratum corneum for enhanced transdermal agent delivery therethrough. The active agent to be delivered is associated with one or more of the microprojections, usually by coating the microprojections with the formulation or by the use of a reservoir that communicates with the stratum corneum after the microslits are formed.
The current manufacturing and packaging processes, however, are problematic, especially where the microprojections are coated with the formulation by drying the formulation on the microprojections, as described in U.S. patent application Publication No. 2002/0128599. The formulation is usually an aqueous formulation. During the drying process, all volatiles, including water are mostly removed, however, the final solid coating still contains typically about 3% water. The presence of water can lead to deterioration of the biologically active agent in the formulation because of hydrolysis.
The current manufacturing and packaging processes are also problematic because oxygen is present during each phase. While the manufacturing phase is a relatively short period of time, the packaging and storage phase can be quite lengthy. Storage times of transdermal delivery systems are likely to be for lengthy periods of time before they are used (i.e., extended shelf life of several months is not uncommon). The biologically active agents in the coatings, therefore, are subject to oxidation and deterioration. For purposes of this application, reference to the term “package” or “packaging” will be understood to also include reference to “storage” or “storing”.
Accordingly, physical stabilization, especially minimizing the exposure of the biologically active agent formulations over time to oxidation and hydrolysis, is an important step in assuring efficacy of the therapeutic agents, particularly when the mode of delivery of the therapeutic agent is via a transdermal delivery device having a plurality of microprojections coated with an agent containing biocompatible coating.
It would therefore be desirable to provide compositions of and methods for formulating and delivering biologically active agents having enhanced physical stability.
It would be further desirable to provide compositions of and methods for formulating and delivering biologically active agents wherein deterioration of the biologically active agent from oxygen and/or water is minimized and/or controlled.
It would be further desirable to provide compositions of and methods for formulating and delivering biologically active agents that exhibit maximal or optimal shelf lives.